Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease

Abstract

Drug transporter expression and function at the blood-brain barrier is altered in Alzheimer's disease (AD). However, the impact of AD on the expression of transporters and metabolizing enzymes in peripheral tissues has received little attention. The current study evaluated the expression of drug transporters and metabolizing enzymes in the small intestine and liver from 8- to 9-month-old female wild-type (WT) and APPswe/PSEN 1dE9 (APP/PS1) transgenic mice, a widely used AD model, using a quantitative targeted absolute proteomics (QTAP) approach. Furthermore, the general morphological appearance of the liver was assessed by immunohistochemistry, and lipid content was visualized using Oil Red O staining. The small intestines of APP/PS1 mice exhibited a significant 2.3-fold increase in multidrug resistance-associated protein 2 (Mrp2), a 1.9-fold decrease in monocarboxylate transporter 1 (Mct1), and a 3.6-fold increase in UDP-glucuronosyltransferase (Ugt) 2b5 relative to those from WT mice based on QTAP analysis. While the liver from APP/PS1 mice exhibited no changes in drug transporter expression, there was a 1.3-fold elevation in cytochrome P450 (Cyp) 51a1 and a 1.2-fold reduction in Cyp2c29 protein expression, and this was associated with morphological alterations including accumulation of hepatocyte lipids. These studies are the first to demonstrate that the protein expression of transporters and metabolizing enzymes important in oral drug absorption are modified in a mouse model of familial AD, which may lead to altered disposition of some orally administered drugs in AD.

Glucuronidation as a metabolic barrier against zearalenone in rat everted intestine

“…In general, enzymes of the UGT2B family glucuronidate steroid hormones [50]. UGT1A1, 1A7, 1A8, and 2A3 are highly expressed in the rodent intestine, especially the proximal intestine [4,38]. A study using human liver and intestinal microsomes reported that UGT1A1, 1A3, 1A8, and 2B7 exhibited high activity against ZON [40].…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…According to data available in the World Guide for Drug Use and Pharmacogenomics [55] and the EuroPharmaGenics (EPG) database [56] concerning central nervous system (CNS) drugs (Figure 1), the best-known genes of the pharmacogenetic machinery involved in the processing of antiepileptic, antidepressant, anxiolytic, hypnotic, sedative, antiparkinsonian, and antipsychotic drugs are mechanistic and metabolic genes, and poorly investigated genes are those involved in pathogenic mechanisms, transporters, and pleiotropic genes ( Figure 1). Globally, 74% pathogenic, 97% mechanistic, 94% metabolic, 68% transporter, and 40% pleiotropic genes have so far been associated with CNS drug efficacy and safety [103].…”

“…CNS drugs are major substrates of CYP3A4 (71%), CYP3A5 (37%), CYP2D6 (60%), CYP2C19 (45%), and CYP1A2 enzymes (44%); inhibitors of CYP3A4 (22%), CYP2D6 (23%), CYP2C19 (20%), CYP1A2 (17%), and CYP2C9 (15%); and inducers of CYP2C9 (9%), CYP2D6 (7%), CYP3A4 (5%), CYP1A2 (4.5%), CYP2A6 (4.5%), and CYP2B6 (3.7%). Major transporters of CNS drugs are ABCB1 (29%), SLCA1 (20%), SLC6A4 (20%), CLCNs (15%), SLC6A3 (12%), and SLC6A2 (11%) ( Figure 3) [103].…”

“…Other transporters responsible for the influx-efflux of neuroleptics are KCNH2 (22%); KCNE1 and KCNE2 (18%); KCNQ1 (18%); and SLC6A2, SLC6A4, and SCN5A (11%). Haloperidol is associated with 31 pharmagenes, Olanzapine is associated with 28, and Thioridazine is associated with 27 [55,103].…”

Impact of reduced P‐glycoprotein function on digoxin concentrations in patients with dementia

“…8,37 While there has been considerable research focused on potential changes in drug transporters at the BBB in AD, little attention has been given to determining whether similar changes occur in peripheral organs in patients with AD. Significant changes in P-gp expression in peripheral organs were not observed in a mouse model of familial AD compared to wild-type mice based on proteomic analyses 41 ; however, species differences in transporter function and regulation necessitate investigating the impact of AD on P-gp function in humans. 42 Recent reports indicate a potential role of systemic inflammation in the pathogenesis of AD 43,44 and, since inflammatory mediators can change the expression and function of transporters, 45 it is possible that altered expression and function of P-gp may also occur in peripheral organs.…”